The overall objective of this proposal is to characterize the dynamics and molecular mechanisms of protein folding. We seek to determine the characteristic rates and underlying molecular mechanisms of the fundamental processes, including chain collapse, secondary structure formation, and formation of specific tertiary interactions. The basic questions we plan to address include: What are the fundamental dynamics, transition state structures and folding mechanisms of ultrafast folding proteins? Can ultrafast folding proteins be made to fold without crossing a free energy barrier (downhill folding)? What is the role of residual structure in the denatured state, and does such structure speed folding? Do peptide models and ultrafast folding subdomains exhibit the same folding behavior in the context of the full protein? These questions are the subject of intense scrutiny and debate in the current protein folding literature. We propose a close interaction between experiment and simulation to answer these questions. We have designed experimental approaches to quantitatively test the predictions of MD simulations of ultrafast folding proteins. In turn, we expect MD simulations to motivate new experiments, or help in the interpretation of experimental observables. We expect such a close interplay between experiment and theory to greatly benefit both, and ultimately improve our understanding of how proteins fold. PUBLIC HEALTH RELEVANCE Understanding how a protein folds to its native, biologically active structure continues to be a central problem of modern biology, with important practical consequences for rational protein design, protein structure prediction and folding related disease states. The aggregation and deposition of misfolded proteins, sometimes the consequence of a single point mutation, is a common feature of neurodegenerative disorders as diverse as Alzheimer's disease, Parkinson's disease, prion diseases, Huntington's disease, and motor neuron disease. The proposed work will provide new understanding of how proteins fold, and what goes wrong when they misfold and cause disease.